1096 replies to this topic

[Andey]

I was never 100% sure what it was. But after a few months my ALT was totally normal again, even though I went back on AKG.

I think that a lot of things can cause fibrosis in the liver. For example anything that encourages cell proliferation, like GDF11, Oxytocin, etc if that cell division is accompanied with raised inflammation. Like forcing a wound to heal too rapidly causes scarring. So perhaps a solution is to accompany a mitotic stimulus with an anti inflammatory. It's all guesswork at this stage.

I'll look at my liver enzymes again in the Spring.

 

  I dont sure 'fibrosis' is necessarily a relevant word here)

 

My ALT dropped pretty quickly, in line with what one can expect with completely removing the source of the problem. Numbers halved in 2.5 days(I was scared a bit so did a recheck), next time I did a test at 3 weeks and it was in the middle of NR)

 

Could be a reaction to some tainted supplement or food too, TBH I would not have thought about AKG if I haven't read your post here

 

My main takeaway is that I need to test more frequently)

Edited by Andey, 12 December 2021 - 11:02 AM.

[QuestforLife]

My ALT dropped pretty quickly, in line with what one can expect with completely removing the source of the problem. Numbers halved in 2.5 days(I was scared a bit so did a recheck).

My main takeaway is that I need to test more frequently)

Mine took months to fall back to normal...I agree on the testing.

I cannot report significant liver issues caused by (Ca)AKG at 1000mg/d for many months but I was concurrently on 400mg/d SAMe, often boosted by 1000 mg/d TMG so they may have neutralized any potential deleterious action.
ALT was 10.

SAMe or TMG sounds like a smart bet for anyone taking lots of supplements

[aribadabar]

I was not aware of the CaAKG adverse effect possibility - I have taken them for their intended purpose - emotional support, methyl donors because I am homozygous for MTHFR and general liver help.

It was more of a coincidence than a targeted "antidote".

[johnhemming]

QuestforLife,

Glycine is described as the main inhibitory neurotransmitter for the brainstem and spinal cord, while GABA is the main inhibitory neurotransmitter for the brain. One can hypothesize that GABA might be more effective than glycine to counter the excitatory effects of glutamate downstream of AKG, but I don't know the dose.

It is argued that GABA does not get across the Blood Brain Barrier.  There are also people that disagree with this on a practical basis.

[QuestforLife]

It is argued that GABA does not get across the Blood Brain Barrier.  There are also people that disagree with this on a practical basis.

 

As has been discussed, this is now somewhat of a mute point, as my testing revealed I have very LOW glutamine levels. Therefore anything used to counteract glutamate would not be effective - and indeed in the long run once any placebo effect wore off, none of my interventions in this direction helped me (although you could argue Vit C and glycine have benefits in and of themselves). 

 

Since I have been taking L-glutamine with my AKG I feel much better. It is still a mystery how it got so low, I can only suppose it was down to my prodigious used of telomerase activators and things like GDF11, which cause increased cellular proliferation and may use up glutamine (as described in my previous post #717). This may be a mechanism by which increasing telomerase decreases demethylase activity, and puts a brake on cellular differentiation and division. 

[QuestforLife]

NMN increases telomere length
Cross posted from else where on the telomere section of the forum...

Very interesting, thank you.

https://www.frontier...021.756243/full

I thought I'd say a brief word on this paper as it was mentioned on a related thread some time ago.

In this paper paper they chose to look at the effects of NMN, amongst other things, on telomere length. Even better, they didn't just look at mice, but at people too, who took 300mg of NMN a day.

The increase in telomere length on peripheral blood cells (lymphocytes and monocytes) was impressive, reaching around 100% extension after several months dosing. This is the biggest extension I've seen, even beating TAM818 (see results on the Defytime website). Epitalon achieved something similar, but it was in vitro.

Is there precedence for this? Yes, previously I discussed how NAMPT upregulation increased telomerase (see https://pubmed.ncbi....h.gov/25926556/ and also post #471). This makes sense as in the current paper they found nicotinamide metabolism was upregulated.

It is also possible that NMN is having this effect through telomerase independent means, reduction of oxidative stress, for example. But unfortunately the paper didn't look at telomerase. We do see guanine metabolites increase, so it's possible more telomeres were being built (G is the most common base in the TTAGGG structure).

The paper also suggests reductions in bacteria in the gut may be responsible. I guess this is possible, if this is sparing the immune system extra work when those bacteria escape into circulation, you would expect telomeres in these cells (and only these cells) to benefit.

Edited by QuestforLife, 21 December 2021 - 10:27 AM.

[dlewis1453]

Results of a 5-Year N-of-1 Growth Hormone Releasing Hormone Gene Therapy Experiment

 

https://www.liebertp...9/rej.2021.0036

 

"Here presented for the first time are results showing persistence over a 5+ year period in a human who had a hormone gene therapy administered to muscle. This growth hormone releasing hormone (GHRH) therapy was administered in two doses, a year apart, with a mean after the second dose of 195 ng/mL (13 × normal, σ = 143, σM = 34, max = 495, min = 53). This level of GHRH therapy appears to be safe for the subject, although there were some adverse events. Insulin-like growth factor 1 levels were little affected, nor were the growth hormone test results, showing no indications of acromegaly for the hormone homologue used. Heart rate declined 8 to 13 bpm, persistent over 5 years. Testosterone rose by 52% (σ = 22%, σM = 6%). The high-density lipoprotein/low-density lipoprotein ratio dropped from 3.61 to mean 2.81 (σ = 0.26, σM = 0.057, max = 3.3, min = 2.5), and triglycerides declined from 196 mg/dL to mean 94.4 mg/dL (σ = 21.9, σM = 5.0, min = 59, max = 133, min = 59). White blood cell counts increased, however, the baseline was not strong. CD4 and CD8 mean increased by11.7% (σ = 11.6%, σM = 3.3%, max = 30.7%, min = −9.6%) and 12.0% (σ = 10.5%, σM = 3.0%, max = 29.1%, min = −6.7%), respectively. Ancillary observations comprise an early period of euphoria, and a dramatic improvement in visual correction after the first dose, spherical correction from baseline (L/R) −2.25/−2.75 to −0.25/−0.5. Over the next 5 years, correction drifted back to −1.25/−1.75. Horvath PhenoAge was cut 44.1% post-treatment. At completion, epigenetic age was −6 years (−9.3%), and telomere age was +7 months (+0.9%)."

[dlewis1453]

Results of a 5-Year N-of-1 Growth Hormone Releasing Hormone Gene Therapy Experiment

 

At completion, epigenetic age was −6 years (−9.3%), and telomere age was +7 months (+0.9%)."

 

The full paper is behind a pay wall. I would like to read the paper, to confirm my understanding of the abstract. My understanding is that about 4-5 years after the start of the gene therapy, the subject's epigenetic age was 6 years lower than before the treatment, and the subject's telomere age was 7 months higher than before the treatment.  This would mean that the subject's epigenetic age reduction was very impressive, while also treading water with telomere age, which itself is also impressive. Growth Hormone Releasing Hormone is a fairly cheap, easily purchased peptide. I wonder what results someone could achieve from regularly injecting GHRH, and how it would compare to the GHRH gene therapy. 

 

Testosterone also increased as a result of the GHRH gene therapy, which is good for quality of life. 

[QuestforLife]

The full paper is behind a pay wall. I would like to read the paper, to confirm my understanding of the abstract. My understanding is that about 4-5 years after the start of the gene therapy, the subject's epigenetic age was 6 years lower than before the treatment, and the subject's telomere age was 7 months higher than before the treatment. This would mean that the subject's epigenetic age reduction was very impressive, while also treading water with telomere age, which itself is also impressive. Growth Hormone Releasing Hormone is a fairly cheap, easily purchased peptide. I wonder what results someone could achieve from regularly injecting GHRH, and how it would compare to the GHRH gene therapy.

I remember reading about Brian Hanley years and years ago. Good that he's got published and with George Church no less.

What he was doing was growth hormone gene therapy, rather than injecting a recombinant protein. But you're right, you'd expect some similar benefits from more regular growth hormone injections. Wasn't that what they did with Greg Fahy's trial? But he also added Metformin to counter the high insulin growth hormone can cause.

Reversal of epigenetic aging and immunosenescent trends in humans

Epigenetic “clocks” can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age‐related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (−2.5‐year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from −1.6 year/year from 0–9 month to −6.5 year/year from 9–12 month. The GrimAge predictor of human morbidity and mortality showed a 2‐year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.

Source:https://dx.doi.org/1...1111/acel.13028

[dlewis1453]

But you're right, you'd expect some similar benefits from more regular growth hormone injections. Wasn't that what they did with Greg Fahy's trial? But he also added Metformin to counter the high insulin growth hormone can cause.
 

 

Greg Fahy injected straight growth hormone into his subjects. In this case, the substance that was boosted was not growth hormone, but a precursor - "growth hormone releasing hormone" - a hormone produced in the hypothalamus which stimulates the pituitary gland to produce and release growth hormone. Just theorizing, but one benefit of increasing growth hormone releasing hormone, rather than growth hormone directly, may be that the pulsatile secretion of growth hormone would be preserved, so side effects may be minimized. I am not sure, however. 

[Fafner55]

Update on the effect of AKG on epigenetic age 

Continuing epigenetic self-tests posted here, I took 500 mg arginine alpha-ketoglutarate (AAKG) 2x/day for 50 days to see if this dose might be effective in reducing epigenetic age without side effects. Previously, AAKG at 1000 mg 2x/day made me feel tired and depressed. This time, at 500 mg, I did not experience side effects but also lost ground in reverting my epigenetic age.

 

Test Date         (Epigenetic age - Chronological age), years

12/17/2020.... -10.45      Baseline before epigenetic treatments

02/17/2021.... -10.32      Turnbuckle stem cell protocol every 10 days (6 times total) with 120 mg gotu kola. During this period I did 1 fasting mimicking diet.

04/13/2021.... -12.58      Turnbuckle stem cell protocol every 10 days (6 times total).

06/08/2021.... -13.05      Autophagy (1 time) - for 5 days took 2 tsp/day of liposomal trehalose + 250 mg centrophenoxine 2x/day + 20 mg astaxanthin 2x/day.  Mitophagy (1 time) - for 7 days took 500 mg Urolithin A 1x/day + 20 mg astaxanthin 2x/day. Separately I did 1 fasting mimicking diet.

09/22/2021.... -15.30      500 mg AAKG 2x/day for 22 days, followed by 1000 mg AAKG + 15000 IU vitamin A  + 400 mg liposomal vitamin C 2x/day for 12 days.

12/08/2021.... -11.75      500 mg AAKG 2x/day for 50 days.

 

[kurt9]

Nice! We now have a second confirmation that Turnbuckle's protocol works.

 

BTW, I know from my experience that the mitochondrial fission/fusion protocol works.

[Moondancer]

I am mostly surprised how any reductions in epigenetic age that Fafner's test showed after he had started taking 2grams of AAKG, not just seem to reverse within 3 months after Fafner reduced his intake, but his earlier reductions in epigenetic age also reversed. I'm not sure what to think of this. How reliable are these tests? 

Edited by Moondancer, 08 January 2022 - 07:44 AM.

[Fafner55]

We don't know the extent DNAm is downstream of other factors, such as environmental and lifestyle influences or an infection or injury or disease. 

I can add that I was careful not to take other supplements while doing this AAKG self-test, and tried to maintain a constant lifestyle and diet. 

[QuestforLife]

The tests aren't that accurate. I've seen various figures from 2-5years claimed depending on the test. So fluctuations smaller than this are to be expected.

However, I've tested many times with DNAm Age and TruMe Labs and I never deviated much from my chronological age until I started AKG. And moreover, both tests gave similar results when, on occasion, I used them within a short time period.

So I conclude that if you test regularly, you'll can have some confidence in your results.

[QuestforLife]

Same thing. I havent checked my liver enzymes in a while (became lazy with all this covid stuff), but recently rechecked and ALT was above 100 (AST was higher than NR too).

I've done some more research into this now, and based on a large European wide study, higher TET2 levels were found to be associated with elevated ALT.

Notably, the values of ALT showing association with high TET2 levels were
mainly below the upper limit for conventional “normal” ALT range but quite over the one of the updated “healthy” ALT range calculated on individuals having other clinical parameters within reference range.

Source: doi: 10.18632/aging.101022

The authors speculate that perhaps higher TET2 is necessary to address liver damage - but directionality is not established; it could be the other way around.

Just something to bear in mind for those of us looking to increase the activity of the demethylases.

Edited by QuestforLife, 08 January 2022 - 10:48 PM.

[QuestforLife]

What are  epigenetic aging tests actually measuring?

 

Thinking about AKG and liver damage and the connections between ROS, DNA damage and methylation and demethylation has suddenly made many things relating to aging clear to me. Amongst them was what epigenetic aging tests are actually measuring.

 

When DNA damage occurs as a result of ROS (or when the DNA has to multiply for cell division), methylation has to be removed from the genome. It then has to be put back on by methylases (DNMTs). Then the demethylases (TETs) have to go around and clean up the methylation that has been added to places it shouldn’t have. So there are various points of intervention: ROS sequestering, which happens through endogenous creation of glutathione and supporting molecules; DNMTs, which are fed methyl groups by SAMe, and the TETs that require AKG and also, control of ROS.

 

 

You can see from the figure above [1] that Glutathione and SAMe production compete; so this is a finely balanced process. If ROS gets just a little out of hand, the DNMTs will have a hard time catching up - and upregulating them for too long would result in reduced glutathione as well as more work for the TETs. Given that this process is going on constantly, with antioxidants running around trying to quench ROS, and DNMTs going around trying to restore some semblance of control to the genome, and the TETs then clearing up after the DNMTs, you can easily imagine that certain genomic locations will be more likely to gain or lose ‘improper’ methylation and this is what is being measured by methylation ‘clocks’. Given enough time this would be fixed and the system would catch up, but another round of ROS is incoming, so the process falls behind.

 

This is why global demethylation increases with age, but methylation of certain locations increases. It is yet not clear why certain locations are more likely to gain methylation, or why many of these are shared between species[2]. But it is clear why increasing AKG would decrease epigenetic age, because it is helping the demethylases to catch up with the last stage of the process of genomic repair. So what epigenetic tests are actually measuring is not biological age exactly, but the rate at which genomic repair is being accomplished, and giving you an age at which that is typical.

 

This explains why cellular senescence and methylation age are parallel processes, because even when repair is fully accomplished, there is a lag in the restoration of a fully functioning genome and this is measured by the accumulation of improper methylation states that has not yet been returned to normal.

 

It also explains why long telomeres/active telomerase can cause an acceleration of epigenetic age, despite leading to reduced senescence. It is because longer telomeres allow faster cellular division, necessitating more cycles of demethylation-remethylation-demethylation.  Even telomerase immortalised cells in vitro accumulate these changes; what is probably required to fix this is slower cellular division.

 

Species with high rates of endogenous ROS and/or fast growth rates will fall behind in the demethylation-remethylation cycle more quickly, hence their faster epigenetic aging. Clearly rapamycin shows the benefits of slowing this down. And endogenous, mitochondrial antioxidants should also have benefits, though it is not yet clear how much slack there is in the system - increasing or reducing DNA damage rates by a small amount wouldn’t necessarily have an effect on epigenetic age unless it was sufficient to affect the relative rate of the methylation part of the cycle. Similarly it is not clear yet whether supplying glutathione precursors, such as in the GlyNAC trial [3], would eventually reduce epigenetic age, or whether they would need to be combined with methyl donors and AKG.

 

Returning to telomeres, in many ways my experiments using telomerase activators along with AKG is a test of the above hypothesis. If I am able to prolong cellular proliferation but stop the accumulations of the methylation clock, then I will have succeeded in addressing two primary expressions of aging in the human body. Looking at the outstanding results of the GlyNAC trial, I am tempted to increase my consumption of glutathione precursors in order to stop any age related rise in ROS and DNA damage rates.

 

Bottom Line

 

Epigenetic aging tests are most likely measuring the speed of your genomic repair machinery to re-establish pre-damage (or pre-division) gene expression as measured by methylation, and giving you an output age for which that rate is common.

 

[1] DOI:10.1093/nutrit/nuv022

[2] doi: https://doi.org/10.1...21.01.18.426733

[3] https://doi.org/10.1002/ctm2.372

[QuestforLife]

Filling in some of the gaps in my idea that epigenetic aging tests are measuring the lag in re-establishing correct methylation patterns after DNA repair or replication...

 

For replication the process is straight forward but not exactly as I guessed. The parent strand does not lose its CpG methylation, but the daughter strand has none (obviously), so after replication it needs to have it added by DNMT1 to match what is on the other strand. (Aside: I wonder if a test could be done to compare strand methylation). 

 

 

DNA methylation occurs in the context of what are called CpG; that is, a C (Cytosine) followed by a G (Guanine). Because C and G are the Watson-Crick pair for each other, the sequence on the opposite strand will also be CG. Usually, both Cs are methylated, which turns out to be rather critical for maintenance of methylation.

DNA replication occurs through a semi-conservative mechanism, which means each old, original strand is copied and paired with a new strand. The new strand has no methylation on it, however; it is at this point that the enzyme DNA methyltransferase (DNMT1, specifically) comes into play. DNMT1 finds the CpGs methylated on one strand ("hemimethylated") and methylates the other strand, providing complete inheritance.

source: https://biology.stac...-is-methylated 

Further explanation here: https://www.intechop.../chapters/38732

 

 

The process is not so clear cut for DNA repair. In fact it appears that DNA damage to the guanine next to a methylated cytosine actually prevents DNA repair. I would assume that in the majority of cases this must be repaired, otherwise cellular senescence would be rampant, therefore demethylation must be happening, but I can't find proof of that at this time. 

 

 

 The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. While the conditions leading to early life hypo or hyper methylation of specific genes are not known, these changes can impact gene expression and imprint susceptibility to oxidative DNA damage in the aged brain. doi: 10.1016/j.freeradbiomed.2009.02.006

 

 

Indeed this paper suggests that the large number of mutations in the human P53 gene when exposed to carcinogens is due to methylated cytosines, and that this creates 'hot spots' of DNA damage.

 

 

Cytosine methylation determines hot spots of DNA damage in the human P53 gene   Strong and selective formation of adducts occurred at guanines in CpG sequences of codons 157, 248, and 273, which are the major mutational hot spots in lung cancer...These results show that methylated CpG dinucleotides, in addition to being an endogenous promutagenic factor, may represent a preferential target for exogenous chemical carcinogens. The data open new avenues concerning the reasons that the majority of mutational hot spots in human genes are at CpGs. doi: 10.1073/pnas.94.8.3893

 

 

 

Edited by QuestforLife, 13 January 2022 - 12:38 PM.

[Andey]

Interesting study (preprint) that Sinclair tweeted

Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain | bioRxiv

They digged into the effects of exercise and parabiosis on aging clocks

Looks like exercise demethylates and parabiosis works through increasing methylation, both selectively.

 

We directly compared the genes responding to either or both of these interventions in a cell type responding to both interventions (aNSC-NPCs) (Fig. 5b). Clock genes in aNSC-NPCs that responded to heterochronic parabiosis were mostly genes that increased in expression with aging (such as those associated with a type I interferon response) (Fig. 5b, right panel, Extended Data Fig. 6b, bottom panel). In contrast, clock genes in aNSC-NPCs that responded to exercise were mostly genes that decreased in expression with aging (such as those associated with transmembrane transport) (Fig. 5b, left panel, Extended Data Fig. 6b, top panel). We also examined the overlap between differentially expressed genes in aNSC-NPCs as a function of age and in response to parabiosis and exercise (see Methods). There was minimal overlap between parabiosis- and exercise-responsive genes, suggesting that these interventions impact the aging transcriptome through different mechanisms (Fig. 5c). Young blood specifically reduced interferon stimulated genes (including the shared gene Ifi27) (Fig. 5c, d). Exercise actually increased some inflammation genes (Ifi27) (Fig. 5c), but reversed the age-associated decline of several genes involved in proliferation and neurogenesis, including Dbx2 which is implicated in age-related SVZ neurogenic decline85 (Fig. 5c).

 

[QuestforLife]

Interesting study (preprint) that Sinclair tweeted
Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain | bioRxiv
They digged into the effects of exercise and parabiosis on aging clocks
Looks like exercise demethylates and parabiosis works through increasing methylation, both selectively.

According to this Horvath study, the CpG sites that change most with age across many species, are mainly locations that GAIN methylation. There are some locations that lose methylation, but they are by FAR in the minority.

See Fig 1A here: https://doi.org/10.1...021.01.18.42673 and attached.
Sites that gain Methylation are red and those that lose it are blue. Genes most affected were those involved in development/differentiation.

That is why the study you report is surprising. I will read the study. But for now I'll take it with a pinch of salt. But if it is true, then it suggests that parabiosis is missing the most important part of aging.

Attached Thumbnails

• 

Edited by QuestforLife, 23 January 2022 - 07:15 PM.

[QuestforLife]

Comment on gonadal rejuvenation by GDF11

 

 

Abstract: Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11, has been shown to have rejuvenation and antiaging properties, but little information is available regarding the role of GDF11 in reproductive system to date. In this study, we first confirmed the bioavailability of recombinant GDF11 (rGDF11) by oral delivery in mice. We also showed that dietary intake of rGDF11 had little influence on body and gonadal (ovary/testis) weights of recipient mice, indicating their general condition and physiology were not affected. Based on these findings, we started to test the function of rGDF11 in ovary and testis of mice and to explore the underlying mechanisms. It was found that to some extent, rGDF11 could attenuate the senescence of ovarian and testicular cells, and contribute to the recovery of ovarian and testicular endocrine functions. Moreover, rGDF11 could rescue the diminished ovarian reserve in female mice and enhance the activities of marker enzymes of testicular function (sorbitol dehydrogenase and glucose-6-phosphate dehydrogenase) in male mice, suggesting a potential improvement of fertility. Notably, rGDF11 markedly promoted the activities of antioxidant enzymes in the ovary and testis, and remarkably reduced the levels of lipid peroxidation, protein oxidation, and reactive oxygen species (ROS) in the ovary and testis. Collectively, these results suggest that GDF11 can protect ovarian and testicular functions of aged mice via slowing down the generation of ROS through enhancing activities of antioxidant enzymes.

https://doi.org/10.1093/gerona/glab343

 

 

With thanks to dlewis1453 for acquiring and sharing the paper with me. I have added some personal notes on my experiences with GDF11 within the text.

 

The paper is somewhat obscure. The research was carried out in China and published by Oxford University Press on behalf of the Gerontological Society of America. The main aim of the work was to look at the effect of exogenous GDF11 on markers of reproductive health in aged male and female mice. The authors were also previously responsible for developing a highly specific GDF11 antibody, which has proven the decline of GDF11 with age (there was some controversy over this because of its similarity with GDF8).

 

Of note, the increase of circulating GDF11 achieved in these mice was from 500 pg/ml to 630 pg/ml, a increase not likely to stimulate GDF8 receptors (personal note: I can no longer inject GDF11 without sharp increases in BP; presumably my levels are now considerably elevated from normal).

 

Remarkably the authors injected the recombinant GDF11 into normal mouse feed and dosed them orally at ~1mg/kg/day for 4 weeks and it was bioavailable, as shown by increases in serum levels at 3 and 6 hours after feeding, but removed by 18 hours. The mice fed GDF11 were 12 months old (middle aged). I find it remarkable what improvements were found in only a 1 month study. I wonder if a supplement manufacturer will take the leap and produce an oral GDF11 supplement? 

 

No change in body weight was observed using GDF11 (note I experience an increase in appetite and an increase in weight, injecting GDF11).

 

50% of control female mice had irregular cycles (the precursor to menopause in human females), but only 33% of the GDF11 dosed group did. Estradiol and progesterone had declined markedly in aged female mice but this was mostly restored in the mice treated with GDF11. Note: this was not treating mice all their lives to prevent these changes; it was treating already middle aged mice to restore functionality. Relevant to this, active/growing follicle count was increased by GDF11 administration. Looking at the health of egg cells in detail, control mice oocytes had swollen mitochondria and lipid accumulation in the cytoplasm. GDF11 mice had smaller mitochondria with visible, functioning cristea, and reduced lipid drop accumulation.

 

Moving onto male mice, aged male mice had only one third of the testosterone level of young mice; mice treated with GDF11 were around halfway in between the two (personal note: I am more aggressive the day after injecting GDF11). Looking at various RNAs, it appeared that GDF11 was working via stimulating testosterone production. Sorbitol dehydrogenase (SDH) and glucose-6-phosphate dehydrogenase (G6PD) are important enzymes for testosterone production and they were upregulated by GDF11.

 

Lipofuscin accumulation in the testes and ovaries of aged male and female mice increased in controls compared to young mice, but was reduced somewhat by GDF11.

 

Lipid peroxidation and protein oxidation were decreased in the ovaries and testes of treated male and female mice compared to controls.

 

Glutathione peroxidase, Superoxide dismutase and catalase were elevated in the ovaries and testes of GDF11 treated mice compared to controls, and overall ROS levels were reduced.

 

It is interesting that the authors found that GDF11 was so effective at decreasing ROS. Though most ROS centric theories look at direct damage from ROS, I expect future studies will find an epigenetic connection via demethylases (I have found AKG to hugely decrease the amount of GDF11 I can tolerate).

 

I have attached several screenshots of figures from the paper if the reader wants to verify some of the statements I have made above.

Attached Thumbnails

• 

Edited by QuestforLife, 04 February 2022 - 10:37 AM.

[dlewis1453]

Great analysis of the paper, thank you. It is exciting to see evidence of GDF11's  beneficial effect on the body, and in particular its effect on the reproductive system and hormonal health. 

 

I have a few other research points to run past you, that might be relevant to your anti-aging protocol. 

 

1. Younging: The first point is Vince Giuliano's latest research on "Younging" by activating the expression of the histone deacetylase JDJM3. Vince has put together the below list of protocols to accomplish this JDJM3 activation. 
 

i. Red and near-infrared light biomodulation, 

ii. Dietary supplements which activate the expression of JDJM3 and also control and limit chronic inflammation,

iii. VARIOXIA. Induction of variations in systemic oxygen levels,

iv. Infusions of umbilical cord blood plasma,

v. VAGUS nerve stimulation, electrical or physical, including applications of the Inflammatory Reflex.

 

https://www.anti-agi...-to-the-series/

 

Given your recent posts on the involvement of ROS in aging, I had been wondering what types of ROS reducing interventions could have synergy with your protocol, and I had settled on red light as a topic to investigate. I was pleasantly surprised when just a week later I saw that Vince posted an entire essay on red light activating JDJM3 as part of his Younging series. What I like about points (i), (iii), and (v) above is that they are active lifestyle interventions, in the league of exercise, that could combine well with your protocol. Points (ii) and (iv) may already have overlap with your protocol. 

 

2. Mitochondrial Uncoupling with DNP: Could ROS reduction be further optimized in your protocol through the introduction of intermittent mild mitochondrial uncoupling? THIS study titled "Mitochondrial uncoupling as a regulator of life-history trajectories in birds: an experimental study in the zebra finch," states the following:

 

"Mitochondria have a fundamental role in the transduction of energy from food into ATP. The coupling between food oxidation and ATP production is never perfect, but may nevertheless be of evolutionary significance. The ‘uncoupling to survive’ hypothesis suggests that ‘mild’ mitochondrial uncoupling evolved as a protective mechanism against the excessive production of damaging reactive oxygen species (ROS)."

 

A man with mild persistent fatigue posted in a group on Facebook about how he administered low dose (3mg) DNP to himself to activate mitochondrial uncoupling, and experienced great benefits. I have posted his entire account of his experience in an attached pdf. Some quick googling showed me that DNP is being studied for its potential longevity benefits, and new mitochondrial uncouplers are being investigated.

 

3. New study on the epigenetics of naked mole rate aging: 

This study appeared on the Longecity front page. It is interesting to see some of the aging mechanisms of such a long lived rodent. According to this study, TERT plays an important role in naked mole rate aging. 

 

https://www.longecit...-other-mammals/

Attached Files

•  Low Dose DNP Anecdote.pdf   122.07KB   111 downloads

Edited by dlewis1453, 04 February 2022 - 05:11 PM.

[QuestforLife]

Great analysis of the paper, thank you. It is exciting to see evidence of GDF11's  beneficial effect on the body, and in particular its effect on the reproductive system and hormonal health.

I have a few other research points to run past you, that might be relevant to your anti-aging protocol.

1. Younging: The first point is Vince Giuliano's latest research on "Younging" by activating the expression of the histone deacetylase JDJM3. Vince has put together the below list of protocols to accomplish this JDJM3 activation.

i. Red and near-infrared light biomodulation,
ii. Dietary supplements which activate the expression of JDJM3 and also control and limit chronic inflammation,
iii. VARIOXIA. Induction of variations in systemic oxygen levels,
iv. Infusions of umbilical cord blood plasma,
v. VAGUS nerve stimulation, electrical or physical, including applications of the Inflammatory Reflex.

https://www.anti-agi...-to-the-series/

Vince has numerous very in-depth posts. In terms of anything actionable, he has clearly shown that anti-inflammatories can protect you in old age. But I haven't seen any evidence he has reversed age, either epigenetically or via telomeres.

 

 

Given your recent posts on the involvement of ROS in aging, I had been wondering what types of ROS reducing interventions could have synergy with your protocol, and I had settled on red light as a topic to investigate. I was pleasantly surprised when just a week later I saw that Vince posted an entire essay on red light activating JDJM3 as part of his Younging series. What I like about points (i), (iii), and (v) above is that they are active lifestyle interventions, in the league of exercise, that could combine well with your protocol. Points (ii) and (iv) may already have overlap with your protocol.

2. Mitochondrial Uncoupling with DNP: Could ROS reduction be further optimized in your protocol through the introduction of intermittent mild mitochondrial uncoupling? THIS study titled "Mitochondrial uncoupling as a regulator of life-history trajectories in birds: an experimental study in the zebra finch," states the following:

"Mitochondria have a fundamental role in the transduction of energy from food into ATP. The coupling between food oxidation and ATP production is never perfect, but may nevertheless be of evolutionary significance. The ‘uncoupling to survive’ hypothesis suggests that ‘mild’ mitochondrial uncoupling evolved as a protective mechanism against the excessive production of damaging reactive oxygen species (ROS)."

A man with mild persistent fatigue posted in a group on Facebook about how he administered low dose (3mg) DNP to himself to activate mitochondrial uncoupling, and experienced great benefits. I have posted his entire account of his experience in an attached pdf. Some quick googling showed me that DNP is being studied for its potential longevity benefits, and new mitochondrial uncouplers are being investigated.

Very interesting. I did some research into uncoupling when I was on a keto diet. Here is an interesting paper on the subject:

 

 

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health

Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone β-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations.
https://www.hindawi....e/2018/5157645/

I expect some of Vince’s suggestions like red light and oxygen levels fall into the category of mitohormesis. I am unsure how I feel about it. When I was on keto I had LESS energy, not more. But I can imagine some individuals with long term damaged mitochondria could benefit from this kind of thing. I do think that lifespan is set by mitochondrial ROS production levels however, I just don’t know how easily we can reduce this and still function.

3. New study on the epigenetics of naked mole rate aging:
This study appeared on the Longecity front page. It is interesting to see some of the aging mechanisms of such a long lived rodent. According to this study, TERT plays an important role in naked mole rate aging.

https://www.longecit...-other-mammals/

 

I am unsure about this study. Epigenetic aging without biological aging? For example, they state methylation of TERT gene promoters and increases with age, but telomeres do not shorten. This implies this methylation does not affect telomerase expression. So, it accumulates but has no effect? More work is required to clarify. Are naked mole rats truly non-aging? I think they probably are, but the accumulate stochastic changes that do not direct limit lifespan. Definitely a species to study further. 

[QuestforLife]

Latest results

Between Sept 21 and January 22 I continued taking AKG; Ca-AKG (liposomal) for about a month, then a short break, then AAKG (liposomal) for about 20 days. Dose was >1g per day for 5 days in every 7.

I dropped Vit C but continued Vit A. I did not add Berberine back in due to worries about telomere shortening. I continued to take telomerase activators during this period, as per usual.

My results have improved back to a delta of -6 years compared to my chronologicalage (see chart 2017-present).

So it appears that liposomal is more effective than capsules, but not hugely.

Future plans. I have several new additions to include in the next iteration. Chief among them is uridine.

Ps, I took another liver enzyme test during this period, and results were normal.

Attached Thumbnails

• 

[QuestforLife]

A new thesis

A certain number of cells is required to maintain function, be that BP and endothelial cells, or reaction times and neurons. It could be said that aging is the process by which insufficient numbers of new cells are produced such that whilst function does not cease altogether, it declines.

So perhaps our aim in fighting aging, should be the production of greater numbers of cells? There seems to be various ways to achieve this that have already been pioneered on Longevity: for example my own statin/sartan protocol, Turnbuckle's Stem Cell protocol, or GDF11.

Then again many here are concerned with biological aging clocks like those based on methylation or on telomere length.

Creating and proliferating cells may not improve these markers. For example it is obvious that without telomerase activation, cellular proliferation must result in reduced telomere length, depleting our future 'bank of life'.

If telomerase is supplied then we may fall afoul of the other clock, methylation. What do you think happens with many more rounds of cellular division? More DNA repair, followed by rounds of methylation via DNMTs and then demethylation 'clean up' via TETs; the imperfection of this process all but guarantees the acceleration of the methylation clock when cells divide more.

I believe it may be possible to create a 'conditionally immortalised' pool of progenitor cells in the blood. Such a pool, once differentiated, could cure many ills in the old body. But I am almost certain that creating such cells would lead to an acceleration of the methylation clock to the tune of 5 or even 10 years! Who would take such a therapy if I offered it?

Let us take another path: suppose I take a powerful telomerase activator and also a powerful mTOR inhibitor. Too much of the latter and you'd get sick. No cell division and no chance for telomerase to act either. A little less mTOR inhibition and suddenly, long telomeres! But having sufficiently accurate biomarkers to judge the sweet spot might be beyond us. Too far the other way is also a possibility. Let us all take glutamate and growth hormone; there may be many benefits, but watch your telomeres shrink away.

I've said enough for now. The main takeaway is that aging clocks need careful interpretation. Getting older or younger by a clock is not necessarily the same as getting older or younger for real. We are starting to get control of our cellular division processes. We must use this power carefully if we are to use it to grow young.

[dlewis1453]

I read several different pieces of research recently that I believe are interconnected and may provide an opportunity for an actionable longevity strategy. In this thread we have been concerned with stem cells throughout the body, but maybe we should take a moment to focus on a key population of stem cells within the hypothalamus that appear to influence body-wide aging. 

 

1.  This paper suggests that Josh Mitteldorf's theory of a centrally located aging timekeeper in the hypothalamus is correct: "Hypothalamic stem cells control ageing speed partly through exosomal miRNAs"

 

"It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs."  

 

https://www.nature.c...othalamus-mice/

 

2. What interventions could potentially prolong the healthy and longevity of these hypothalamic stem cells? Maybe low-dose Deprenyl (Selegiline)? The following paper shows that Deprenyl has a beneficial effect on the hypothalamus and helps restore youthful hormonal activity- "Deprenyl treatment restores serum insulin-like growth factor-I (IGF-I) levels in aged rats to young rat level"

 

"We studied the effects of treatment with (-)-deprenyl, a monoamine oxidase B inhibitor, on plasma levels of insulin-like growth factor-I (IGF-I) (as indicator of growth hormone (GH) secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase - the rate-limiting enzyme in the biosynthesis of catecholamines - in the hypothalamus and hypophysis of old male rats. Male Wistar rats (22 months old) were treated with 2 mg deprenyl/kg body weight s.c. three times a week for 2 months. At the end of the treatment period, blood was collected for measurement of plasma IGF-I levels by radioimmunoassay (RIA). The concentrations of dopamine, serotonin (5-HT) and their main metabolites were determined by high performance liquid chromatography (HPLC) with electrochemical detection, and the tyrosine hydroxylase content in hypothalamus and hypophysis was determined by enzyme-linked immunoabsorbent assay (ELISA). (-)-Deprenyl treatment produced a pronounced increase in dopamine and 5-HT in both the hypothalamus and hypophysis (P < 0.01). The main dopaminergic metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), decreased in hypothalamus but not in hypophysis, and treatment had no effect on the concentration of 5-hydroxyindole-3-acetic acid (5-HIAA). The tyrosine hydroxylase activity and tyrosine hydroxylase content increased in hypothalamus and hypophysis (P < 0.05). In the hypophysis the increase in tyrosine hydroxylase activity was consistent with the increase in tyrosine hydroxylase amount. Moreover, (-)-deprenyl treatment restored the IGF-I plasma levels in old rats to a concentration similar to those found in young animals. Postulated anti-aging effects of (-)-deprenyl could hence be due to restoration of hypothalamic hormones such as GH."  

 

https://www.selegiline.com/gh.html

 

3. If Deprenyl does have this effect on hypothalamic stem cells, we should expect Deprenyl administration to contribute to longevity? It turns out that Deprenyl  has reliably increased maximum lifespan in rodents by 20-30% in several studies. Deprenyl also has benefits for cognition, mood, and brain health generally, but the focus of this post is on its potential lifespan benefit. 

 

https://pubmed.ncbi.....gov/27777099/  https://lmreview.com/an-interview-with-joseph-knoll-m-d/  https://www.benbest.com/lifeext/deprenyl.html  https://www.nature.com/articles/mp2016127

 

4. Further Research - the comprehensive website https://www.selegiline.com/ contains a large compilation of research on the various effects of seligiline/deprenyl. Other notable causes of action include the increase of superoxide dismustase in key regions of the brain. The increase in SOD in the brain could also benefit the key stem cells in the hypothalamus. Additionally, it could be productive to research how GDF-11 and Klotho, two compounds we have discussed at length on this thread and which have beneficial effects on telomerase and stem cell health, affect the key population of stem cells in the hypothalamus, as well as the hypothalamus as whole and the brain generally. 

 

Edited by dlewis1453, 01 March 2022 - 10:16 PM.

[QuestforLife]

I read several different pieces of research recently that I believe are interconnected and may provide an opportunity for an actionable longevity strategy. In this thread we have been concerned with stem cells throughout the body, but maybe we should take a moment to focus on a key population of stem cells within the hypothalamus that appear to influence body-wide aging. 

 

1.  This paper suggests that Josh Mitteldorf's theory of a centrally located aging timekeeper in the hypothalamus is correct: "Hypothalamic stem cells control ageing speed partly through exosomal miRNAs"

 

"It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs."  

 

https://www.nature.c...othalamus-mice/

 

2. What interventions could potentially prolong the healthy and longevity of these hypothalamic stem cells? Maybe low-dose Deprenyl (Selegiline)? The following paper shows that Deprenyl has a beneficial effect on the hypothalamus and helps restore youthful hormonal activity- "Deprenyl treatment restores serum insulin-like growth factor-I (IGF-I) levels in aged rats to young rat level"

 

"We studied the effects of treatment with (-)-deprenyl, a monoamine oxidase B inhibitor, on plasma levels of insulin-like growth factor-I (IGF-I) (as indicator of growth hormone (GH) secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase - the rate-limiting enzyme in the biosynthesis of catecholamines - in the hypothalamus and hypophysis of old male rats. Male Wistar rats (22 months old) were treated with 2 mg deprenyl/kg body weight s.c. three times a week for 2 months. At the end of the treatment period, blood was collected for measurement of plasma IGF-I levels by radioimmunoassay (RIA). The concentrations of dopamine, serotonin (5-HT) and their main metabolites were determined by high performance liquid chromatography (HPLC) with electrochemical detection, and the tyrosine hydroxylase content in hypothalamus and hypophysis was determined by enzyme-linked immunoabsorbent assay (ELISA). (-)-Deprenyl treatment produced a pronounced increase in dopamine and 5-HT in both the hypothalamus and hypophysis (P < 0.01). The main dopaminergic metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), decreased in hypothalamus but not in hypophysis, and treatment had no effect on the concentration of 5-hydroxyindole-3-acetic acid (5-HIAA). The tyrosine hydroxylase activity and tyrosine hydroxylase content increased in hypothalamus and hypophysis (P < 0.05). In the hypophysis the increase in tyrosine hydroxylase activity was consistent with the increase in tyrosine hydroxylase amount. Moreover, (-)-deprenyl treatment restored the IGF-I plasma levels in old rats to a concentration similar to those found in young animals. Postulated anti-aging effects of (-)-deprenyl could hence be due to restoration of hypothalamic hormones such as GH."  

 

https://www.selegiline.com/gh.html

 

3. If Deprenyl does have this effect on hypothalamic stem cells, we should expect Deprenyl administration to contribute to longevity? It turns out that Deprenyl  has reliably increased maximum lifespan in rodents by 20-30% in several studies. Deprenyl also has benefits for cognition, mood, and brain health generally, but the focus of this post is on its potential lifespan benefit. 

 

https://pubmed.ncbi.....gov/27777099/  https://lmreview.com/an-interview-with-joseph-knoll-m-d/  https://www.benbest.com/lifeext/deprenyl.html  https://www.nature.com/articles/mp2016127

 

4. Further Research - the comprehensive website https://www.selegiline.com/ contains a large compilation of research on the various effects of seligiline/deprenyl. Other notable causes of action include the increase of superoxide dismustase in key regions of the brain. The increase in SOD in the brain could also benefit the key stem cells in the hypothalamus. Additionally, it could be productive to research how GDF-11 and Klotho, two compounds we have discussed at length on this thread and which have beneficial effects on telomerase and stem cell health, affect the key population of stem cells in the hypothalamus, as well as the hypothalamus as whole and the brain generally. 

 

Thanks for the extensive post. I have read the paper you list under (1) before and to be honest although I am sympathetic to the theory, the results did not blow me away. If aging really were programmed from the hypothalamus, then they would have achieved more impressive results. Of course this could be only part of a pro aging signal. But I am a little weary of all this talk of pro and anti aging factors in the blood after all the E5 fanfare. My feeling is that these kind of interventions will make people healthier but they'll still die around on schedule, though I could be wrong (and in fact would like to be proved wrong).

 

This thread is based on investigating the role of telomeres and telomerase in the aging process, and finding out if this can be used to extend life and health. Of course I take lots of diversions into other areas of stem cell science or epigenetics, if that area impinges on telomeres. For example what would happen if stem cells experienced no telomere shortening? Then you'd probably get selection for stem cells that divided symmetrically and didn't differentiate. And I have dealt with this possibility in numerous post. Things like GDF11 are also relevant here as they cause more differentiation. They also active telomerase (a little), but there is a danger here that long term administration would keep you healthier but at the cost of long life. The same goes for other stem cell stimulation protocols like Turnbuckle's.    

 

Deprenyl is interesting though, it is a substance I've never tried. 

[dlewis1453]

Here is a paper from 2021 titled "Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity." 

 

Abstract: 

 

It has been reported that growth differentiation factor 11 (GDF11) protects against myocardial ischemia/reperfusion (IR) injury, but the underlying mechanisms have not been fully clarified. Considering that GDF11 plays a role in the aging/rejuvenation process and that aging is associated with telomere shortening and cardiac dysfunction, we hypothesized that GDF11 might protect against IR injury by activating telomerase. Human plasma GDF11 levels were significantly lower in acute coronary syndrome patients than in chronic coronary syndrome patients. IR mice with myocardial overexpression GDF11 (oe-GDF11) exhibited a significantly smaller myocardial infarct size, less cardiac remodeling and dysfunction, fewer apoptotic cardiomyocytes, higher telomerase activity, longer telomeres, and higher ATP generation than IR mice treated with an adenovirus carrying a negative control plasmid. Furthermore, mitochondrial biogenesis-related proteins and some antiapoptotic proteins were significantly upregulated by oe-GDF11. These cardioprotective effects of oe-GDF11 were significantly antagonized by BIBR1532, a specific telomerase inhibitor. Similar effects of oe-GDF11 on apoptosis and mitochondrial energy biogenesis were observed in cultured neonatal rat cardiomyocytes, whereas GDF11 silencing elicited the opposite effects to oe-GDF11 in mice. We concluded that telomerase activation by GDF11 contributes to the alleviation of myocardial IR injury through enhancing mitochondrial biogenesis and suppressing cardiomyocyte apoptosis.

 

https://www.nature.c...419-021-03954-8

 

 

[QuestforLife]

Here is a paper from 2021 titled "Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity."

I discussed this in post 709 (https://www.longecit...-24#entry911292).

What they show here is that it is the mitochondrial function of telomerase that is beneficial to the injured heart, which agrees with what I have discovered with telomerase activators increasing exercise tolerance.

[Castiel]

NMN increases telomere length
Cross posted from else where on the telomere section of the forum...

I thought I'd say a brief word on this paper as it was mentioned on a related thread some time ago.

In this paper paper they chose to look at the effects of NMN, amongst other things, on telomere length. Even better, they didn't just look at mice, but at people too, who took 300mg of NMN a day.

The increase in telomere length on peripheral blood cells (lymphocytes and monocytes) was impressive, reaching around 100% extension after several months dosing. This is the biggest extension I've seen, even beating TAM818 (see results on the Defytime website). Epitalon achieved something similar, but it was in vitro.

Is there precedence for this? Yes, previously I discussed how NAMPT upregulation increased telomerase (see https://pubmed.ncbi....h.gov/25926556/ and also post #471). This makes sense as in the current paper they found nicotinamide metabolism was upregulated.

It is also possible that NMN is having this effect through telomerase independent means, reduction of oxidative stress, for example. But unfortunately the paper didn't look at telomerase. We do see guanine metabolites increase, so it's possible more telomeres were being built (G is the most common base in the TTAGGG structure).

The paper also suggests reductions in bacteria in the gut may be responsible. I guess this is possible, if this is sparing the immune system extra work when those bacteria escape into circulation, you would expect telomeres in these cells (and only these cells) to benefit.

 

Sirtuin 4 is said to lengthen telomeres, resveratrol lengthens telomeres by activating telomerase through sirtuin 4.  It is likely that high NAD+ levels would also increase sirt4 activity,